FCER1A

Abstract: Background Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation. Objective We sought to ascertain the genetic risk factors that lead to IgE dysregulation. Methods A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS). Seventy of the top single nucleotide polymorphisms (SNPs) were selected based on P values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with 5 independent populations from the Cooperative Health Research in the Region of Augsburg cohort, the British 1958 Birth Cohort, and the Childhood Asthma Management Program cohort. Results Thirteen SNPs located in the region of 3 genes, FCER1A , signal transducer and activator of transcription 6 (STAT6) , and IL13 , were found to have genome-wide significance in the FHS cohort GWAS. The most significant SNPs from the 3 regions were rs2251746 ( FCER1A , P = 2.11 × 10 −12 ), rs1059513 ( STAT6 , P = 2.87 × 10 −8 ), and rs1295686 ( IL13 , P = 3.55 × 10 −8 ). Four additional gene regions, HLA-G , HLA-DQA2 , HLA-A , and Duffy blood group, chemokine receptor (DARC) , reached genome-wide statistical significance in a meta-analysis combining the FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene. Conclusion This GWAS of the FHS cohort has identified genetic loci in HLA genes that might have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of the known susceptibility loci FCER1A , STAT6 , and IL13 for the dysregulation of total IgE.

Abstract: Immunoglobulin E (IgE) mediated immune responses seem to be directed against parasites and neoplasms, but are best known for their involvement in allergies. The IgE network is tightly controlled at different levels as outlined in this review. Genetic determinants were suspected to influence IgE regulation and IgE levels considerably for many years. Linkage and candidate gene studies suggested a number of loci and genes to correlate with total serum IgE levels, and recently genome-wide association studies (GWAS) provided the power to identify genetic determinants for total serum IgE levels: 1q23 (FCER1A), 5q31 (RAD50, IL13, IL4), 12q13 (STAT6), 6p21.3 (HLA-DRB1) and 16p12 (IL4R, IL21R). In this review, we analyse the potential role of these GWAS hits in the IgE network and suggest mechanisms of how genes and genetic variants in these loci may influence IgE regulation.

Abstract: Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4 + T cells express IgE receptor FceR1, at much higher levels than do CD8 + T cells. IgE induces CD4 + T-cell production of IL6 and IFN-c, but reduces their production of IL10. FceR1 deficiency (Fcer1a / ) protects apolipoprotein E-deficient (Apoe / ) mice from angiotensin-II infusioninduced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4 + T cells (but not CD8 + T cells), MCs, and macrophages from Apoe / mice, but not those from Apoe / Fcer1a / mice, increases AAA size and plasma IL6 in Apoe / Fcer1a / recipient mice. Biweekly intravenous administration of an anti-IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe / mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4 + T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs.

Abstract: We found a novel polymorphism, −66T/C, in the promoter region of human Fc e RI α, the specific component of the high affinity receptor for IgE (FceRI), which is essential for the cell surface expression of FceRI and the binding of IgE Ab. When the effect of the single nucleotide replacement on the promoter function was analyzed, the transcription activity of the T allele promoter was found to be higher than that of the C allele promoter, and was markedly up-regulated by the overexpression of GATA-1 when compared with the C allele promoter. This is probably because the promoter with T at −66 has an additional GATA-1-binding motif in the region, which may assure higher affinity of the transcription factor to the promoter. In accordance with this, EMSA actually indicated that GATA-1 bound to the T allele probe (−80/−59) with the affinity higher than that to the C allele probe. Statistical analysis suggested that a significant portion of nonallergic individuals has heterozygous −66T/C genotype, while most of allergic individuals have homozygous −66T/T genotype in Japanese population. Our findings for the first time demonstrate the presence of FceRIα polymorphism related to the allergic diseases.